SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

Pilar Esteve (1) , Africa Sandonis (1) , Marcos Cardozo (1) , Jordi Malapeira (1) , Carmen Ibanez (1) , Inmaculada Crespo (1) , Severine Marcos (1) , Sara Gonzalez (1) , Maria Luisa Toribio (1) , Joaquin Arribas (1) , Akihiko Shimono (1) , Isabel Guerrero (1) , Paola Bovolenta (1)

1 Development and Differentiation

It is well established that embryonic mouse retinal neurogenesis requires Notch signaling activation but is independent of the Wnt signaling pathway. Surprisingly, we show here that genetic inactivation of Sfrp1 and Sfrp2, two postulated Wnt antagonists, perturbs retinal neurogenesis. We solved this apparent paradox by demonstrating that in Sfrp1-/-;Sfrp2-/- embryonic retinas, Notch signaling is transiently upregulated because Sfrps bind and downregulate ADAM10 metalloprotease activity, a critical step in Notch activation. Consistently, the proteolysis of other ADAM10 substrates, including APP, is altered in Sfrp mutants, whereas pharmacological ADAM10 inhibition partially rescues the Sfp1/2 null retinal phenotype. Conversely, ectopic Sfrp1 expression in the Drosophila wing imaginal disc prevents Notch targets' expression, which is completely restored by the co-expression of Kuzbanian, the Drosophila ADAM10 homolog. Together these data support a novel function for Sfrps as inhibitors of the ADAM10 metalloprotease, which might have important implications in pathological events, including cancer and Alzheimer disease.

Mots clés: Development; Differentiation; Sensory Systems; Signal Transduction; signalling; cell biology

Pilar Esteve, Africa Sandonis, Marcos Cardozo, Jordi Malapeira, Carmen Ibanez, et al.. SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis. Nature Neuroscience, 2011, ⟨10.1038/nn.2794⟩. ⟨hal-00630412⟩